Experimental studies done this past year have demonstrated the V3 domain to be part of a contiguous conformational epitope as evidenced by the virus' ability to escape a V3-specific monoclonal antibody without changing any of the primary amino acids (a.a.) in the antibody binding site. Neutralizing antibody subsequently directed at the V3 region following infection is correlated in the selection of escape mutants which ultimately demonstrate V3-specific a.a. changes. The virus therefore has two mechanisms identified for evading the humoral immune system. Clonal expansion of a virus population is rapidly observed in other acute or experimental infections in humans or chimpanzees, leading initially to a monotypic (type-specific) neutralizing response. This neutralizing response to the incoming virus appears to also clonally expand due to cross-reactivity in the invariant V3 domain of the emerging escape mutants. Similar results are observed with envelope immunization, suggesting an "original antigenic sin" - like phenomena may be operational during infection or vaccination. Fractionation studies using pooled human HIV-1 serum demonstrate that the majority of neutralizing activity is found associated with V3 and the CD4-binding site on gpl20. The potency of broader CD4mediated neutralization, however, is poorer than V3 and demonstrates strain-variability. Viruses passaged in vitro in primary lymphocyte cell lines select the most replication-competent virus subpopulations. Escape mutants arise from less replication-competent virus subpopulations. Mechanisms are operating in addition to a strong humoral response(s) in human immunodeficiency virus (HIV)-l infected chimpanzees to restrict and possibly control the virus in this species. These include T8 suppressor activity, differences in their CD4 molecule and "relative" lack of infectability of their peripheral blood monocytes by HIV-1. This model appears to be very instructive for efficacy immunogenicity testing and challenge for examining the sterilizing immunity of a prototype HIV-1 vaccine. The use of the model for disease prevention is in serious doubt.